Iodinated contrast media are well-known compounds widely used in x-ray imaging diagnostic techniques. Suitable examples of the said compounds include, for instance, diatrizoate, iothalamate, ioxithalamate, metrizoate, iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iodixanol, iosarcol, iogulamide, ioglunide, iogluamide, acetrizoate, iodamide, iocetamide and metrizamide, which are all monomeric; while, for example, ioxaglate, iotrolan, iotasul, iodipamide, iocarmate, iodoxamate, iotroxate, iotrolan, and the like, are dimers. Other examples of iodinated contrast agents are described, for instance, in WO 94/14478 (Bracco).
As a common feature, their chemical structure shares a triiodinated aromatic nucleus which provides the enhanced contrast effect.
The said compounds may be prepared by a variety of routes, some of which comprise the aromatic iodination of given substrates, in particular suitable anilines, so as to provide the corresponding 2,4,6-triiodoaniline derivatives, to be further converted and processed to the final compounds.
Useful precursors for the preparation of the above compounds are also 3,5-disubstituted phenols, which undergo triiodination on the available 2, 4 and 6 positions, at first, so as to give rise to the corresponding 3,5-disubstituted-2,4,6-triiodophenols. These latter, in turn, may be further converted and processed through the so-called Smile's rearrangement, to the expected final compounds.
For a general reference to the above synthetic route and Smile's rearrangement see, for instance, WO 88/09328, WO 97/05097 and WO 00/32561 (Bracco).
Iodination on the phenol ring may occur at the ortho and para free positions, i.e. at the 2, 4 and 6 positions, according to the well-known electrophilic substitution mechanism, thus leading to the triiodinated ring.
The iodination step, in particular, may be performed according to several methods known in the art.
For instance, it can be carried out by using solutions of iodine chloride (ICl) in concentrated hydrochloric acid (HCl) or, alternatively, by means of analogous iodinating agents such as, for instance, KICl2 or NaICl2 in aqueous solution; see, for a general reference, WO 92/14695 (Guerbet) or U.S. Pat. No. 5,013,865 (Mallinckrodt).
The above methods suffer from major drawbacks due to the limited storage life of the iodinating agents and to their corrosive properties. In addition, the presence of chlorine atoms may lead to side-reactions and, thus, to the undesired formation of chlorine side-products, which may affect reaction yields and purity of the final compounds.
The above problems may be well addressed according to an alternative path comprising electrochemical iodination of suitable aromatic nuclei. Electrochemical iodination involves, in particular, the anodic formation of I+ ions from an iodine source, for instance I2 itself, in an electrolytic cell, substantially as per the following Scheme:I2→2I++e−and the thus formed I+ cations may then act as iodinating agents on the aromatic nucleus of the targeted compound.
Apart from molecular iodine, a variety of iodides such as alkali metal iodides and even hydriodic acid or their mixtures may be employed as well to electrochemically originate I+ species.
Remarkably, however, electrochemical iodination from I2 source advantageously provides for two moles of iodinating species originating from 1 mole of iodine source. In addition, another main advantage offered by said method is that the iodinating specie may be generated on need, thus avoiding the storage of corrosive reagents. Moreover, as no chlorine source is present, no chlorination by-products affecting the purity of the final compound may be thus obtained.
The electrochemical iodination of aromatic substrates is known in the art as reported, for instance, in J. Am. Chem. Soc., Vol. 98, No. 6, 1976, pages 1515-1519; and EP 828705 (Nycomed Imaging As).
According to EP 828705, in particular, it is disclosed a process for the preparation of monomeric or dimeric triiodoaniline compounds comprising the electrochemical iodination of 3,5-disubstituted anilines or 3,3′-disubstituted-5,5′-linked bisanilines.
As far as phenols and derivatives thereof are concerned, instead, U.S. Pat. No. 3,833,490 discloses a process for the preparation of herbicides comprising the electrochemical iodination of 4-hydroxybenzonitrile in the presence of IO− ions, so as to provide the corresponding mono- or di-iodinated derivatives bearing iodine atoms in positions 3 and/or 5.
Remarkably, the above iodination process is directly carried out within the electrolytic cell, that is under the oxidizing conditions existing at the anodic compartment, as the presence of a substituent (e.g. cyano group) in para position with respect to the phenolic hydroxy group may render the above substrate less susceptible of oxidative degradation.
However, by even carrying out the iodination step outside the electrolytic cell, the iodination of phenol with a iodinating specie electrochemically generated, did not provide the expected results as mixtures of byproducts were instead obtained. Experimental evidence for the same can be found in Comparative Examples 1 and 2 of the following experimental section.
Despite these major drawbacks concerning the electrochemical iodination of phenols, however, we have unexpectedly found that the electrochemical iodination of given 3,5-disubstituted phenols enabled for the preparation of the corresponding triiodinated compounds.